Pyrrolidine orexin receptor antagonists

ABSTRACT

The present invention is directed to pyrrolidine compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999, 98, 437-451). Orexins have also been indicated as playing a role in arousal, reward, learning and memory (Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to pyrrolidine compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein: A is selected from the group consisting of phenyl, naphthyl and heteroaryl;

X is N or CH;

each of R^(1a), R^(1b) and R^(1c) is independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) hydroxyl,     -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1         (wherein if m is 0 or n is 0, a bond is present) and where the         alkyl is unsubstituted or substituted with one to three         substituents independently selected from R⁴,     -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is         unsubstituted or substituted with one to three substituents         independently selected from R⁴,     -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted         or substituted with one to three substituents independently         selected from R⁴,     -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted         or substituted with one to three substituents independently         selected from R⁴,     -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where         the phenyl or naphthyl is unsubstituted or substituted with one         to three substituents independently selected from R⁴,     -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is         unsubstituted or substituted with one to three substituents         independently selected from R⁴,     -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently         selected from the group consisting of:         -   (a) hydrogen,         -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with             R⁴,         -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with             R⁴,         -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with             R⁴,         -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted             with R⁴,         -   (f) phenyl, which is unsubstituted or substituted with R⁴,             and         -   (g) heterocycle, which is unsubstituted or substituted with             R⁴,     -   (11) —S(O)₂—NR¹⁰R¹¹,     -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is         selected from the definitions of R¹⁰ and R¹¹,     -   (13) —CO₂H,     -   (14) —CN, and     -   (15) —NO₂;         R² is selected from hydrogen, C₁₋₆alkyl, and —(C═O)—C₁₋₆alkyl;         R³ is selected from hydrogen and C₁₋₆alkyl;         R⁴ is selected from the group consisting of:     -   (1) hydroxyl,     -   (2) halogen,     -   (3) C₁₋₆alkyl,     -   (4) —C₃₋₆cycloalkyl,     -   (5) —O—C₁₋₆alkyl,     -   (6) —O(C═O)—C₁₋₆alkyl,     -   (7) —NH₂,     -   (8) —NH—C₁₋₆alkyl,     -   (9) —NO₂,     -   (10) phenyl,     -   (11) heterocycle,     -   (12) —CO₂H, and     -   (13) —CN;         R⁵ is selected from the group consisting of:     -   (1) hydrogen,     -   (2) halogen,     -   (3) —CN,     -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or phenyl,     -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or phenyl,     -   (5) —O—C₃₋₆cycloalkyl, which is unsubstituted or substituted         with C₁₋₆alkyl, halogen or phenyl, and     -   (6) —(C═O)—O—C₁₋₆alkyl;         R⁶ is selected from the group consisting of:     -   (1) hydrogen,     -   (2) halogen,     -   (3) —CN,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or phenyl,     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen or phenyl,     -   (6) —O—C₃₋₆cycloalkyl, which is unsubstituted or substituted         with C₁₋₆alkyl, halogen or phenyl, and     -   or R⁵ and R⁶ may be joined together with the carbon atoms to         which they are attached to form a 6-membered aromatic ring,         which is unsubstituted or substituted with one or two C₁₋₆alkyl;         or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia:

wherein A, R^(1a), R^(1b), R^(1c), R², R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia′:

wherein A, R^(1a), R^(1b), R^(1c), R², R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia″:

wherein A, R^(1a), R^(1b), R^(1c), R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib:

wherein R^(1a), R^(1b), R², R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib′:

wherein R^(1a), R^(1b), R², R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ib″:

wherein R^(1a), R^(1b), R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic:

wherein R^(1a), R², R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic′:

wherein R^(1a), R², R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ic″:

wherein R^(1a), R³, R⁵ and R⁶ are defined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A is selected from phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, and pyrazolyl. An embodiment of the present invention includes compounds wherein A is phenyl. An embodiment of the present invention includes compounds wherein A is pyridyl. An embodiment of the present invention includes compounds wherein A is thiophenyl. An embodiment of the present invention includes compounds wherein A is thiazolyl. An embodiment of the present invention includes compounds wherein A is isothiazolyl. An embodiment of the present invention includes compounds wherein A is pyrazolyl.

An embodiment of the present invention includes compounds wherein X is N. An embodiment of the present invention includes compounds wherein X is CH.

An embodiment of the present invention includes compounds wherein Y is O. An embodiment of the present invention includes compounds wherein Y is NH. An embodiment of the present invention includes compounds wherein Y is N(CH₃).

An embodiment of the present invention includes compounds wherein R^(1a), R^(1b) and R^(1c) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) hydroxyl,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl,     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl,     -   (6) heteroaryl, wherein heteroaryl is selected from imidazolyl,         indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,         and triazolyl, which is unsubstituted or substituted with         halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,     -   (7) phenyl, which is unsubstituted or substituted with halogen,         hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,     -   (8) —O-phenyl, which is unsubstituted or substituted with         halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,     -   (9) —CN, and     -   (10) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is         unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,         and —O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R^(1a), R^(1b) and R^(1c) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) hydroxyl,     -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl,     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, hydroxyl or phenyl,     -   (6) —CN, and     -   (7) heteroaryl, wherein heteroaryl is selected from imidazolyl,         indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,         and triazolyl, which is unsubstituted or substituted with         halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds wherein R^(1a), R^(1b) and R^(1c) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen,     -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen,     -   (5) —CN, and     -   (6) heteroaryl, wherein heteroaryl is selected from imidazolyl,         indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,         and triazolyl.

An embodiment of the present invention includes compounds wherein R^(1c) is hydrogen, and R^(1a) and R^(1b) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) fluoro,     -   (3) chloro,     -   (4) bromo,     -   (5) methyl,     -   (6) ethyl,     -   (7) methoxy,     -   (8) trifluoromethyl, and     -   (9) heteroaryl, wherein heteroaryl is selected from imidazolyl,         indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,         and triazolyl.

An embodiment of the present invention includes compounds wherein R^(1c) is hydrogen, and R^(1a) and R^(1b) are independently selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) fluoro,     -   (3) chloro,     -   (4) methyl,     -   (5) methoxy,     -   (6) tetrazolyl, and     -   (7) triazolyl.

An embodiment of the present invention includes compounds wherein R³ is methyl. An embodiment of the present invention includes compounds wherein R³ is (R)-methyl.

An embodiment of the present invention includes compounds wherein R⁵ is selected from the group consisting of:

-   -   (1) hydrogen,     -   (2) halogen,     -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with         halogen,     -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, and     -   (5) —(C═O)—O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R⁵ is selected from the group consisting of: hydrogen, fluoro, methyl, and methoxy.

An embodiment of the present invention includes compounds wherein R⁶ is selected from the group consisting of:

-   -   (1) —CN,     -   (2) halogen,     -   (3) —C₁₋₆alkyl, which is unsubstituted or substituted with         halogen, and     -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with         halogen.

An embodiment of the present invention includes compounds wherein R⁶ is selected from the group consisting of: —CN, methyl, methoxy, and difluoroethoxy.

An embodiment of the present invention includes compounds wherein R⁵ and R⁶ are joined together with the carbon atoms to which they are attached to form a 5-membered lactone ring, which is unsubstituted or substituted with one or two methyl.

Certain embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Formula I shows the structure of the class of compounds without specific stereochemistry.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.

The term “heteroaryl” as used herein includes benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, and wherein the saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ²H and ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N, oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as ³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorine such as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound which is selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual enantiomers or diastereomers thereof.

The present invention is also directed to the use of the compounds disclosed herein as antagonists of orexin receptor activity. The subject compounds and pharmaceutically acceptable salts thereof are useful in a method of antagonizing orexin receptor activity in a subject such as a mammal comprising the administration of an amount of the compound. In addition to primates, especially humans, a variety of other mammals may be administered with a compound of the present invention. The present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof that could be useful in therapy. The present invention may further be directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for antagonizing orexin receptor activity or treating the disorders and diseases noted herein in humans and animals.

A subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof, is generally a mammal, such as a human being, male or female. The amount of compound administered to the subject is an amount sufficient to antagonize the orexin receptor in the subject. In an embodiment, the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound. It is recognized that one skilled in the art may affect neurological and psychiatric disorders associated with orexin receptor activation by treating a subject presently afflicted with the disorders, or by prophylactically treating a subject likely to be afflicted with the disorders, with an effective amount of a compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder. The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to to the subject.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R antagonists may be readily determined without undue experimentation by methodology well known in the art, including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys. Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2 receptor antagonistic activity of the compounds of the present invention was determined in accordance with the following experimental method. For intracellular calcium measurements, Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μl assay buffer containing 1 μM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 μl assay buffer. 30 μl of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 μl, incubated for 5 min and finally 25 μl of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist. For each antagonist, IC50 value (the concentration of compound needed to inhibit 50% of the agonist response) is determined. Alternatively, compound potency can be assessed by a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant (K_(i)) is determined in membranes prepared from CHO cells expressing either the OX1 or OX2 receptor. The intrinsic orexin receptor antagonist activity of a compound which may be used in the present invention may be determined by these assays.

All of the final compounds of the following examples had activity in antagonizing the human orexin-2 receptor in the aforementioned assays with an IC50 of about 0.1 nM to 1500 nM. All of the final compounds of the following examples had activity in the FLIPR assay with an IC50 of about 5 nM to 1500 nM against the orexin-2 receptor. Additional data is provided in the following Examples. Such a result is indicative of the intrinsic activity of the compounds in use as antagonists of orexin-1 receptor and/or the orexin-2 receptor. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively antagonize the orexin receptor if it has an IC50 of less than about 50 μM, or more specifically less than about 1000 nM.

The orexin receptors have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention could therefore potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, including one or more of the following conditions or diseases: sleep disorders, sleep disturbances, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; decreasing nocturnal arousals, especially early morning awakenings; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with the intensity of sleep; increasing sleep maintenance; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, conditions due to drugs which cause reductions in REM sleep as a side effect; fibromyalgia; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep; increasing learning; augmenting memory; increasing retention of memory; eating disorders associated with excessive food intake and complications associated therewith, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity-related disorders overeating, anorexia, bulimia, cachexia, dysregulated appetite control, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; sudden death, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g., children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility dyskinesias, obesity-related gastro-esophageal reflux, hypothalmic diseases, hypophysis diseases, respiratory disorders, such as obesity-hyperventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthetic risk, reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy; diseases or disorders where abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function, including cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders; enhancing memory; increasing memory retention; increasing immune response; increasing immune function; hot flashes; night sweats; extending life span; schizophrenia; muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance-induced mood disorders; affective neurosis; depressive neurosis; anxiety neurosis; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's Chorea; Huntington's disease and Tourette syndrome; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, seizure disorders, absence seisures, complex partial and generalized seizures; Lennox-Gastaut syndrome; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder; dissociative disorders including multiple personality syndromes and psychogenic amnesias; substance-related disorders, substance use, substance abuse, substance seeking, substance reinstatement, all types of psychological and physical addictions and addictive behaviors, reward-related behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, addictive feeding, addictive feeding behaviors, binge/purge feeding behaviors, dependence, withdrawal or relapse from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); appetite, taste, eating or drinking disorders; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia); neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders; attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); headache; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers; Kallman's syndrome (anosmia); asthma; cancer; conditions associated with visceral pain such as irritable bowel syndrome, and angina; eating disorders; urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage; retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache and other diseases related to general orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methods for: enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia and all types of sleep disorders; treating or controlling sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; treating or controlling addiction disorders; treating or controlling psychoactive substance use and abuse; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling diabetes and appetite, taste, eating, or drinking disorders; treating or controlling hypothalamic diseases; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; treating or controlling dysthymic, mood, psychotic and anxiety disorders; treating or controlling depression, including major depression and major depression disorder; treating or controlling bipolar disorder; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian subject which comprises administering to the subject a compound of the present invention.

The subject compounds could further be of potential use in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to the subject, e.g., humans and elderly humans, to obtain effective antagonism of orexin receptors. The dosage range will generally be about 0.5 mg to 1.0 g. per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per subject per day; in another embodiment about 0.5 mg to 200 mg per subject per day; and in yet another embodiment about 5 mg to 50 mg per subject per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day. The compounds may be administered before bedtime. For example, the compounds may be administered about 1 Hour prior to bedtime, about 30 minutes prior to bedtime or immediately before bedtime.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is contemplated. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered in combination with other compounds which are known in the art to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, omortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of the present invention may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed in combination with other compounds which are known in the art, either administered separately or in the same pharmaceutical compositions, including, but are not limited to: insulin sensitizers including (i) PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like); (iii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics, such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like; (e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bile acid absorbers/sequestrants, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iii) proliferator-activater receptor a agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterol acyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide, (v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, and the like, and PPARα agonists as described in WO 97/36579; (g) PPARδ agonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists, such as muraglitazar, and the compounds disclosed in U.S. Pat. No. 6,414,002; (i) anti-obesity agents, such as (1) growth hormone secretagogues, growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, and L-163,255, and such as those disclosed in U.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB 1 receptor antagonists or inverse agonists, such as rimonabant, taranabant, AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO 04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No. 6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8) neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354; 6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332; 6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and 6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCT International Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO 99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO 02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO 04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists, such as those disclosed in WO 01/21577 and WO 01/21169; (10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin receptor antagonists, such as SB-334867-A, and those disclosed in patent publications herein; (13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, and sertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and those disclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and those described in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) 3-hydroxy steroid dehydrogenase-1 inhibitors (P3-HSD-1); (26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (29) ghrelin receptor antagonists, such as those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed in Pept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron); (35) monoamine reuptake inhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid; (37) thyroid hormone 3 agonists, such as KB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin; and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucose transporter inhibitors; (48) phosphate transporter inhibitors; (49) Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)]NPY 24-36, TASP-V, and cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP), and other Y4 agonists such as 1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroid dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and those disclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No. 6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60) amphetamine; (61) benzphetamine; (62) chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane; (79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87) phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs or derivatives thereof, (90) oxyntomodulin and analogs or derivatives thereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists) such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and 5,637,699.

In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed in combination with anti-Alzheimer's agents; beta-secretase inhibitors, such as verubecestat; gamma-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABA_(A) inverse agonists; or neuronal nicotinic agonists.

In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed in combination with acetophenazine, alentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed in combination with a nicotine agonist or a nicotine receptor partial agonist such as varenicline, opioid antagonists (e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene), dopaminergic agents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidate hydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g., Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g., Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors, 11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergic receptor agonists, dopamine receptor agonists, melanocyte-stimulating hormone receptor analogs, 5-HT2c receptor agonists, melanin concentrating hormone receptor antagonists, leptin, leptin analogs, leptin receptor agonists, galanin receptor antagonists, lipase inhibitors, bombesin receptor agonists, neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor antagonists, other orexin receptor antagonists, such as suvorexant, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors, human agouti-related protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists, and pharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed in combination with an anoretic agent such as aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; selective serotonin reuptake inhibitor (SSRI); halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the subject compound may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention may be effective for use in humans.

The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art (e.g. PCT Patent Publications WO2001/68609, WO2004/085403, WO2005/118548, WO2008/147518, WO2009/143033 and WO2010/048012) or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Bn: benzyl; Ac: acetyl; Boc: tert-butyloxy carbonyl; BSA: bovine serum albumin; CbzCl: benzylchloroformate; CDI: carbonyl diimidazole; DCM: dichloromethane; DCE: dichloroethane; DEAD: diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; CH₂Cl₂: dichloromethane; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₃N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; HCl: hydrogen chloride; HOAt: 1-hydroxy-7-aza-benzotriazole; HOBT: hydroxybenzotriazole hydrate; HPLC: high performance liquid chromatography; Hunig's base: N,N-diisopropylethylamine; MeOH: methanol; MgSO₄: magnesium sulfate; MTBE: methyl tert-butyl ether; NaHCO₃: sodium bicarbonate; NaOH: sodium hydroxide; NMM: N-methylmorpholine; PtO₂: platinum oxide; PyClu: 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate; rt: room temperature; SOCl₂: thionyl chloride; T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; THF: tetrahydrofuran; TFA: trifluoracetic acid; X-Phos: 2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropylbiphenyl. The compounds of the present invention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

INTERMEDIATES Intermediate A 2-(1-Cyanocyclopropyl)benzoic acid

Step 1: Methyl 2-(1-cyanocyclopropyl)benzoate (A2)

To a solution of NaH (1.1 g, 26.2 mmol) in DMSO (20 mL) was added compound A1 (2 g, 11.4 mmol); after stirring at room temperature under nitrogen for 1 h, 1-bromo-2-chloroethane (1.8 g, 12.6 mmol) was added, the mixture stirred at room temperature for 2h. The mixture was quenched with ice water (10 mL) and extracted with EtOAc (10 mL×3). The organic layer was combined, dried and concentrated in vacuo to give the crude compound, which was purified by column chromatography on silica gel eluting with (Petroleum Ether/EtOAc 20:1) to give the title compound as a solid. MS (ESI) m/e (M+H+) was detected.

Step 2: 2-(1-Cyanocyclopropyl)benzoic acid

A solution of compound A2 in THF/MeOH/H₂O (3:1:1, 16 mL) was treated with lithium hydroxide in water (3 mL). The mixture was stirred overnight at room temperature. The THF and MeOH were removed in vacuo and the resulting solution acidified to pH ˜1 with HCl (1 N) to give a white crystalline precipitate. The crystals were isolated by filtration, washed with water and dried in vacuo affording intermediate A as a solid. MS (ESI) m/e (M+H⁺): 187.9.

Intermediate B 2-(1-Cyanocyclobutyl)benzoic acid

2-(1-Cyanocyclobutyl)benzoic acid (Intermediate B)

A solution of methyl 2-(cyanomethyl)benzoate (1.07 g, 6.11 mmol) in 10 mL of DMSO was treated with NaH ((0.537 g, 13.44 mmol, 60% dispersion in mineral oil) at room temperature (RT). The mixture was stirred for 30 min., 1-bromo-3-chloropropane (1.06 g, 6.72 mmol) added and the reaction mixture stirred at RT. Et₂O (10 mL) was added, the mixture cooled to 0° C., quenched with water and extracted with Et₂O (75 mL×2). The combined organic fractions were washed with brine (40 mL), dried over Na₂SO₄, filtered and the solvent was evaporated in vacuo. The crude material was purified by silica gel gradient chromatography (0-20% EtOAc in hexanes), providing methyl 2-(1-cyanocyclobutyl)benzoate as an oil.

Methyl 2-(1-cyanocyclobutyl)-benzoate (210 mg, 0.976 mmol) was dissolved in THF (2 mL), MeOH (0.7 mL) and H₂O (0.7 mL) and treated with aq 2M LiOH (1.0 mL, 2 mmol) and the mixture stirred at RT overnight. Additional 2 M LiOH (0.5 mL) and 0.5 mL of MeOH were added and stirring continued for 8 h, followed by a further addition of 2M LiOH (0.5 mL) and stirring for 16h. MeOH and THF were evaporated, the pH of the resulting aqueous solution adjusted to ˜6 with 1 M HCl and extracted with EA (3×75 mL). The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and evaporated in vacuo to give the title compound which was used directly without further purification. LSMS m/z (M+H) 202.1 found, 202.2 required.

Intermediate C 2-(2H-Tetrazol-2-yl)benzoic acid

To a 20 mL microwave tube was charged 2-iodobenzoic acid (1.85 g, 7.46 mmol), cesium carbonate (4.06 g, 12.5 mmol), copper(I) iodide (0.128 g, 0.671 mmol), and DMA (8.0 mL). N,N′-Dimethylglyine (0.131 g, 1.27 mmol) and tetrazole (1.29 g, 18.4 mmol) were added, and the solution was irradiated in a microwave reactor at 100° C. for 1 hour. The reaction was diluted with water and 1 N aqueous sodium hydroxide and washed with EtOAc. The aqueous fraction was acidified with conc. HCl and extracted 2x with EtOAc. The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel gradient chromatography [0-85% (1% acetic acid in EtOAc) in hexanes], providing the title compound. ¹H NMR (400 MHz, CD₃OD): δ 7.72-7.84 (m, 3H), 8.07 (dd, J=7.6, 1.6 Hz, 1H), 8.90 (s, 1H) ppm. LRMS m/z (M+H) 191.1 found, 191.2.

Intermediate D 2-(2H)-1,2,3-Triazol-2-yl)thiophene-3-carboxylic acid

A solution of 2-bromo-3-thiophene carboxylic acid (1.50 g, 7.24 mmol), 1H-1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75° C. for 96 h. The reaction was diluted with water, washed with ether, and acidified with conc. HCl. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], providing the title compound as a solid. LRMS m/z (M+H) 196.2 found, 196.1 required.

Intermediate E Potassium 2-(pyrimidin-2-yl)thiophene-3-carboxylate

A solution of 2-bromo-3-thiophene carboxylic acid (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0° C. and saturated with gaseous HCl. The solution was heated to 60° C. overnight, then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as an oil. LRMS m/z (M+H) 221.1 found, 221.0 required.

A solution of methyl 2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol), 2-(tributylstannyl)pyrimidine (4.36 g, 11.81 mmol), cesium fluoride (4.78 g, 31.5 mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in a pressure vessel was purged subsurface with nitrogen and treated with palladium tetrakis (0.455 g, 0.394 mmol). The mixture was sealed and heated at 120° C. overnight. The reaction was partitioned between EtOAc and water and filtered through celite. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-30% EtOAc in hexanes), providing methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate as a solid. LRMS m/z (M+H) 221.2 found, 221.1 required.

A solution of methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate (0.695 g, 3.16 mmol) and potassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred at RT overnight, then diluted with ether and filtered through a glass frit. The solids were washed with ether, and the filtrate was concentrated, providing the title compound as a solid. LRMS m/z (M+H) 207.3 found, 207.1 required.

Intermediate F 4-[1,2,3]Triazol-2-yl-thiophene-3-carboxylic acid

Step 1: 4-Bromo-thiophene-3-carboxylic acid ethyl ester (F1)

To a solution of 3,4-dibromothiophene (30 g, 0.12 mol) in THF (200 mL) at 0° C. was added i-PrMgCl (2.0 M solution in THF, 77 mL, 0.15 mol), keeping the temperature below 5° C. The resulting mixture was stirred at 0-5° C. for 5 h, ethyl chloroformate (14.4 mL, 0.15 mol) added dropwise with <10° C. and the resulting mixture warmed to RT, stirred overnight and quenched with the sat aqueous NH₄Cl. Most of the THF was then removed in vacuo, water added and the mixture extracted with EtOAc (80 mL×4). The combined organic layers were dried over Na₂SO₄, filtered, the filtrate concentrated in vacuo and the crude product purified by chromatography on silica (Petroleum ether:EtOAc=300:1) to provide the title compound as an oil.

Step 2: 4-Bromo-thiophene-3-carboxylic acid (F2)

To a solution of the product from step 1 (10 g, 43 mmol) in methanol (60 mL) was added sodium hydroxide (3.4 g, 86 mmol) and water (1 mL) and the mixture was stirred at RT overnight. The mixture was concentrated in vacuo, the residue diluted with water (30 mL) and extracted with EtOAc (25 mL×4). The pH of aqueous layer was adjusted to ˜3 with 1M HCl and the aqueous phase extracted with EtOAc (25 mL×4). The combined extracts were dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo to provide the title compound as a solid. LRMS m/z (M+H) 206.9, 208.9 found, 206.9, 208.9 required.

Step 3: 4-[1,2,3]Triazol-2-yl-thiophene-3-carboxylic acid (Intermediate F)

To a mixture of the product from step 2 (7.9 g, 38 mmol), Cs₂CO₃ (24.8 g, 76 mmol) and CuI (2.88 g, 7.6 mmol) in DMF (200 mL) were added 2H-[1,2,3]triazole (5.24 g, 76 mmol) and N,N′-dimethyl-cyclohexane-1,2-diamine (0.9 g, 6.5 mmol) and the mixture was stirred at 110° C. overnight. The cooled mixture was adjusted to ˜pH12 with 1M sodium hydroxide and extracted with EtOAc (50 mL×3). The aqueous layer was adjusted to ˜pH 4 with 1M HCl and extracted with EtOAc (50 mL×4). The extracts was dried over Na₂SO₄, filtered, the filtrate concentrated in vacuo and the residue purified by chromatography on silica (Petroleum ether:EtOAc=10:1) to provide the title compound. LRMS m/z (M+H) 196.0 found, 196.0 required.

Intermediate G 4-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesium carbonate (89.26 g, 274 mmol) and CuI (5.27 g, 27.4 mmol) in DMF (200 mL) were added N,N′-dimethylcyclohexane-1,2-diamine (3.7 mL, 23.3 mmol) and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture was stirred at 110° C. overnight, cooled, concentrated in vacuo and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL×3). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (300 mL×4). The combined organic layers were washed with brine (150 mL×3), dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether:EtOAc=100:1˜5:1) to provide the title compound as a solid. LRMS m/z (M+H) 208.0 found, 208.0 required.

Intermediates H, I, J 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid 5-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid 6-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

Intermediates H, I, J were prepared in a similar manner to that described for Intermediate G, replacing 2-bromo-4-fluorobenzoic acid with the appropriate bromo or iodo substituted fluorobenzoic acids.

Intermediate K 3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step 1: 3-(2H-1,2,3-triazol-2-yl)picolinic acid

To a solution of 3-bromonicotinic acid (1.4 g, 6.93 mmol) in DMSO (14 mL) was added 2H-1,2,3-triazole (0.718 g, 10.40 mmol), cesium carbonate (4.74 g, 14.55 mmol), copper(I) iodide (0.132 g, 0.693 mmol), and N1,N2-dimethylcyclohexane-1,2-diamine (0.099 g, 0.693 mmol) and the reaction mixture sparged with nitrogen and stirred at 120° C. overnight. The cooled reaction mixture was diluted with 1 N NaOH (15 mL) and washed with EtOAc (15 mL). The aqueous layer was acidified with 12 N HCl and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine, dried over NaSO₄, filtered, and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica (0-100% (EtOAc:5% AcOH in EtOAc). The purified fractions were combined and azetroped with toluene (3×100 mL) to give 3-(2H-1,2,3-triazol-2-yl)picolinic acid as a solid. LSMS m/z (M+H) 191.05 found, 191.05 required.

Intermediate L 2-(4-Methyl-1H-pyrazol-1-yl)nicotinic acid

Step 1: 2-(4-Methyl-1H-pyrazol-1-yl)nicotinic acid

To a solution of 2-bromonicotinic acid (1.4 g, 6.93 mmol) in DMSO (14 mL) was added 4-methyl-1H-pyrazole (0.852 g, 10.40 mmol), cesium carbonate (4.74 g, 14.55 mmol), copper(I) iodide (0.132 g, 0.693 mmol), and N1,N2-dimethylcyclohexane-1,2-diamine (0.099 g, 0.693 mmol). The reaction was sparged with nitrogen and heated at 120° C. overnight. The cooled reaction mixture was diluted with 1 N NaOH (15 mL) and washed with EtOAc (15 mL). The aqueous layer was acidified with 12 N HCl and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine, dried over NaSO₄, filtered, and the solvent was evaporated in vacuo. The crude material was purified by chromatography on silica [0-100% (5% AcOH in EtOAc)/hexanes]. The purified fractions were combined and azetroped with toluene (3×100 mL) to give 2-(4-methyl-1H-pyrazol-1-yl)nicotinic acid as a solid. LSMS m/z (M+H) 204.07 found, 204.07 required.

Intermediate M 2-(1H-Pyrazol-1-yl)nicotinic acid

Step 1: 2-(1H-Pyrazol-1-yl)nicotinic acid

To a solution of 2-bromonicotinic acid (1.4 g, 6.93 mmol) in DMSO (14 mL) was added 1H-pyrazole (0.707 g, 10.40 mmol), cesium carbonate (4.74 g, 14.55 mmol), copper(I) iodide (0.132 g, 0.693 mmol), and N1,N2-dimethylcyclohexane-1,2-diamine (0.099 g, 0.693 mmol). The mixture was sparged with nitrogen and heated at 120° C. overnight. The cooled reaction mixture was diluted with 1 N NaOH (15 mL) and washed with EtOAc (15 mL). The aqueous layer was acidified with 12 N HCl and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine, dried over NaSO₄, filtered, and the solvent was evaporated in vacuo. The crude material was purified by silica gel gradient chromatography [0-100% (5% AcOH in EtOAc)/hexanes]. The purified fractions were combined and azetroped with toluene (3×100 mL) to give 2-(1H-pyrazol-1-yl)nicotinic acid as a solid. LSMS m/z (M+H) found, required.

Intermediate P 3-(1H-Pyrazol-1-yl)pyrazine-2-carboxylic acid

Step 1: 3-(1H-Pyrazol-1-yl)pyrazine-2-carboxylic acid (Intermediate P)

To a suspension of sodium hydride (278 mg, 6.95 mmol, 60% in oil) in DMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture stirred at room temperature for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture heated to 60° C. for 2 h. After cooling to RT, water (20 mL) was added and the mixture extracted with 4.7% MeOH in DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give the title compound as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required.

Intermediate Q 3-(Pyridin-2-yl)pyrazine-2-carboxylic acid

Step 1: methyl 3-chloropyrazine-2-carboxylate (Q1)

To a solution of 3-chloropyrazine-2-carboxylic acid (100 mg, 0.63 mmol) in DCM/MeOH (2 mL:0.2 mL) was added TMSCHN₂ (0.47 mL, 0.95 mmol) at RT and the resulting mixture stirred at RT for 2 h. Acetic acid (0.2 mL) was added and the mixture diluted with water (2 mL) and extracted with DCM (4 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give the title compound as a oil. LRMS m/z (M+H) 173.0 found, 173.0 required.

Step 2: Methyl 3-(pyridin-2-yl)pyrazine-2-carboxylate (Q2)

To a solution of the product from step 1 (100 mg, 0.58 mmol) in toluene (2 mL) was added Pd(PPh₃)₄(134 mg, 0.12 mmol) and 2-(tributylstannyl)pyridine (213 mg, 0.58 mmol) at room temperature and the resulting mixture heated to 100° C. overnight. After cooling to RT, the mixture was filtered and 5 mL of aq. KF solution was added to the filtrate. The resulting mixture was stirred for 30 mins and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by chromatography (30% EtOAc in petroleum ether) to provide the title compound as a oil. LRMS m/z (M+H) 216.1 found, 216.1 required.

Step 3: 3-(Pyridin-2-yl)pyrazine-2-carboxylic acid (Intermediate Q)

A solution of the product from step 2 (50 mg, 0.23 mmol) and NaOH (27.8 mg, 0.69 mmol) in 2 mL of methanol and 0.1 mL of water was stirred at RT overnight. After adjusting to pH=5 with 1N HCl, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (8 mL), stirred for 10 mins and filtered. The filtrate was concentrated in vacuum to give the title compound as a solid. LRMS m/z (M+H) 202.1 found, 202.1 required.

Intermediate R 2-(3-Methyl-1,2,4-oxadiazol-5-yl)benzoic acid

Step 1: N-Hydroxy-2-iodobenzimidamide

To a solution of 2-iodobenzonitrile (15 g, 65.5 mmol) in EtOH (262 mL) was added hydroxylamine (12.98 g, 196 mmol) and the mixture heated to 80° C. overnight, cooled and concentrated in vacuo. The crude mixture was diluted with EtOAc (300 mL) and washed with water (300 mL) and brine (300 mL). The organic layer was dried over NaSO₄, filtered, and concentrated in vacuo to give the product used directly in the next step. LRMS m/z (M+H) 263.0 found, 263.0 required.

Step 2: 5-(2-Iodophenyl)-3-methyl-1,2,4-oxadiazole

To 1,1-dimethoxy-N,N-dimethylethanamine (26.4 g, 198 mmol) was added the product from step 1 (26 g, 99 mmol and the mixture stirred at rt for 1 h. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (30 mL), the organic layer dried over NaSO₄, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica (0-20% EtOAc in hexanes), providing 5-(2-iodophenyl)-3-methyl-1,2,4-oxadiazole as an oil. LSMS m/z (M+H) 287.0 found, 287.0 required.

Step 3: Methyl 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate

To a solution of the product from step 2 (19 g, 66.4 mmol) in MeOH (133 mL) and DMSO (133 mL) was added triethylamine (23.1 mL, 166 mmol) and the mixture sparged with nitrogen. PdCl₂(dppf)-CH₂Cl₂ (2.71 g, 3.32 mmol) was added, the mixture was evacuated and placed under an atmosphere of carbon monoxide and stirred overnight at 60° C. The cooled reaction mixture was concentrated in vacuo and diluted with EtOAc (150 mL) and saturated aqueous NaHCO₃. The mixture was filtered over a pad of celite. The filtrated was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (200 mL), dried over NaSO₄ and concentrated in vacuo. The crude material was purified by chromatography on silica (0-60% EtOAc in hexanes), providing the title compound as an oil. LSMS m/z (M+H) 219.1 found, 219.1 required.

Step 4: 2-(3-Methyl-1,2,4-oxadiazol-5-yl)benzoic acid

To a solution of the product from step 3 (10.2 g, 46.8 mmol) in MeOH (187 mL) was added 1 M NaOH (140 mL, 140 mmol) and the mixture stirred at 50° C. overnight. The solution was acidified with 12 N HCl to a pH ˜3 and concentrated to remove MeOH. The mixture was redissolved in EtOAc 200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over NaSO₄, filtered, and concentrated in vacuo to provide the title compound as a solid. LSMS m/z (M+H) 205.1 found, 205.1 required.

Example 1

1-(2-((2R,4R)-4-((4-(2,2-Difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclobutcarbonitrile Step 1: 2-chloro-4-(2,2-difluoroethoxy)pyridine (4)

A solution of 2-chloropyridin-4-ol (1.0 g, 7.72 mmol) in DMF (20 mL) was treated with 1,1-difluoro-2-iodoethane (1.14 mL, 1.92 mmol) and K₂CO₃ (1.6 g, 11.58 mmol)

and heated at 60° C. overnight. The reaction was diluted with EtOAc and washed with saturated, aqu. NaHCO₃, then with brine. The organics were dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by chromatography on silica (0-30% EtOAc in hexanes) to give the title compound as an oil.

Step 2: 4-(2,2-difluoroethoxy)-N-((3R,5R)-5-methylpyrrolidin-3-yl)pyridin-2-amine hydrochloride (5)

A solution of (2R,4R)-tert-butyl 4-amino-2-methylpyrrolidine-1-carboxylate, (Laine, D. et al. ACS Med. Chem. Lett. 2011, 2, 142-147) (1.05 g, 5.24 mmol) and 2-chloro-4-(2,2-difluoroethoxy)pyridine (1.13 g, 5.84 mmol) in 20 mL of toluene was sparged with N₂. Sodium t-butoxide (6.55 ml, 13.11 mmol) was added and after additional N₂ sparging, BrettPhos precatalyst (Strem, CAS#1148148-01-9) added, followed by an additional N₂ sparge. The reaction mixture was heated to 65° C. for 16 h, cooled to RT, diluted with EtOAc and filtered through Celite. Water was added to the filtrate which was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (0-80% EtOAc in hexanes) to give an oil (1.1 g). A solution of this oil (500 mg, 1.4 mmol) was dissolved in DCM and treated with 4M HCl in dioxane (3 ml, 36.5 mmol); the mixture was stirred at RT for 4 hrs and the mixture concentrated in vacuo. The residue was azeotroped twice more with dioxane and the resulting product dried in vacuo overnight to give the title compound, used directly without further purification.

Step 3: (2R,5R)-tert-Butyl 5-(4,5-dihydrooxazol-2-yl)-2-methylpiperidine-1-carboxylate (Example 1)

To a solution of the product from step 2 (18.1 mg, 0.062 mmol) in DMF (1 mL) was added EDC (17.7 mg, 0.092 mmol), HOAt (12.6 mg, 0.092 mmol), DIEA (48 mg, 0.37 mmol) and 2-(1-cyanocyclobutyl)benzoic acid (intermediate B from above) (10 mg, 0.062 mmol) and the mixture stirred at RT for 16 h, poured into water (30 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo and the crude product purified by reverse phase HPLC to provide the title compound. HRMS m/z (M+H) 441.2092 found, 441.2097 required.

TABLE 1 The following compounds were prepared according to the general procedure provided in Example 1, Step 3, and procedures herein, by substituting the appropriate benzoic acid. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 2

1-(2-((2R,4R)-4-((4-(2,2- difluoroethoxy)pyridin-2-yl)amino)-2- methylpyrrolidine-1- carbonyl)phenyl)cyclopropanecarbonitrile Calc'd 427.2, found 427.2 3

(2-(2H-tetrazol-2-yl)phenyl)((2R,4R)-4- ((4-(2,2-difluoroethoxy)pyridin-2- yl)amino)-2-methylpyrrolidin-1- yl)methanone Calc'd 430.2, found 430.2 4

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)- 5-(4-(6-fluoropyridin-2-yl)oxazol-2-yl)-2- methylpiperidin-1-yl)methanone Calc'd 446.1, found 446.1 5

((2R,4R)-4-((4-(2,2- difluoroethoxy)pyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)(2-(pyrimidin-2- yl)thiophen-3-yl)methanone Calc'd 435.1, found 435.1 6

((2R,4R)-4-((4-(2,2- difluoroethoxy)pyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)(2-ethoxypyridin-3- yl)methanone Calc'd 407.2, found 407.2 7

((2R,4R)-4-((4-(2,2- difluoroethoxy)pyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)(2,3-dihydro-1H- inden-4-yl)methanone Calc'd 402.2, found 402.2

Example 8

(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-(quinolin-2-ylamino)pyrrolidin-1-yl)methanone Step 1: (2R,4S)-tert-Butyl 2-methyl-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (6)

To a cooled (0° C.) solution of (2R,4S)-tert-butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate (Mitsumori, S. et al J. Am. Chem. Soc. 2006, 128 1040-1041) (39 g, 0.12 mol) in DCM (500 mL) was added triethylamine (35.69 g, 0.35 mol), followed by dropwise addition of methanesulfonyl chloride (29.74 g, 0.26 mol) and the mixture stirred at RT for 5 h. The mixture was diluted with DCM (500 mL), washed with brine (500 mL), the organic layer dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by column chromatography (9% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 280.1 found, 280.1 required.

Step 2: (2R,4R)-tert-Butyl 4-azido-2-methylpyrrolidine-1-carboxylate (7)

To a solution of the product from step 1 (5.5 g, 19.7 mmol) in DMF (30 mL) was added NaN₃ (2.78 g, 42.8 mmol) at RT. The resulting mixture was stirred at 90° C. overnight, cooled to RT, diluted with water (100 mL) and extracted with EtOAc (100 mL×5). The combined organic layers were washed with brine and sat. aq. NaHCO₃, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo to give the crude product as an oil which was used without further purification. LRMS m/z (M+H) 227.1 found, 227.1 required.

Step 3: (2R,4R)-4-Azido-2-methylpyrrolidine (8)

To a solution of the product from step 2 (4.0 g, 17.7 mmol) in DCM (20 mL) was added TFA (20 mL) dropwise at 0° C. and the resulting mixture stirred at RT overnight. The mixture was concentrated in vacuo to give the crude product as an oil, used directly in the next step without further purification. LRMS m/z (M+H) 127.1 found, 127.1 required.

Step 4: (2-(2H-1,23-Triazol-2-yl)phenyl)((2R,4R)-4-azido-2-methylpyrrolidin-1-yl)methanone (9)

To a solution of the product from step 3 (2.5 g, 19.8 mmol) in DCM (30 mL) at 0° C. were added DIPEA (7.68 g, 59.5 mmol) followed by a solution of 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (3.29 g, 15.9 mmol) in DCM (10 mL) and the resulting mixture stirred at RT overnight. The mixture was washed with brine, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo to give the crude product as an oil which was used without further purification. LRMS m/z (M+H) 298.1 found, 298.1 required.

Step 5: tert-Butyl ((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)carbamate (10)

To a solution of the product from step 4 (5.5 g, 18.5 mmol) in methanol (120 mL) was added Pd/C (1 g) and Boc₂O (6.06 g, 27.8 mmol). The resulting mixture was stirred under H₂ at RT overnight. The mixture was filtered, the filtrate was concentrated in vacuo and the residue purified by chromatography on silica (33% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 372.2 found, 372.2 required.

Step 6: (2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (11)

To a solution of the product from step 5 (3.3 g, 8.9 mmol) in DCM (30 mL) at 0° C. was added TFA (20 mL) dropwise and the resulting mixture stirred at RT for 2 hrs, then concentrated in vacuo. The residue was diluted with DCM (50 mL) and triethylamine added dropwise to pH=8. The mixture was washed with water (30 mL) and extracted with DCM (50 mL×10), the combined organic layers washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica (9% methanol in DCM) to give the title compound as an oil. LRMS m/z (M+H) 272.1 found, 272.1 required.

Step 7: (2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-(quinolin-2-ylamino)pyrrolidin-1-yl)methanone

A mixture of the product from step 6 (100 mg, 0.369 mmol), 2-chloroquinoline (60 mg, 0.369 mmol), Cs₂CO₃ (300 mg, 0.92 mmol), X-phos (35 mg, 0.074 mmol) and Pd₂(dba)₃ (55 mg, 0.055 mmol) in DMF (3 mL) was stirred at 100° C. under N₂ atmosphere for 5 hours. The cooled reaction mixture was filtered and the filtrate purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 399.2 found, 399.2 required.

Example 9

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone Step 1: 2-Chloro-4-(difluoromethyl)pyridine (12)

To a solution of 2-chloroisonicotinaldehyde (6.0 g, 42 mmol) in DCM (100 mL) at 0° C. under N₂ was added DAST (20 g, 126 mmol) and the mixture stirred at 0° C. for 2 hs. Sat. aqueous NaHCO₃ solution was added and the mixture extracted with EtOAc (300 mL×3). The combined organic layers were dried over MgSO₄, filtered, concentrated in vacuo and the crude product purified by chromatography on silica (25% EtOAc in petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 164.1 found, 164.0 required.

Step 2: (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone

To a solution of (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (Example 8 step 6) (500 mg, 1.85 mmol) in THF (10 mL) was added the product from step 1 (201 mg, 1.23 mmol), t-Bu-xphos (253 mg, 0.37 mmol), t-BuOK in THF (3.7 mL, 3.7 mmol, 1.0 mol/L) and Pd(dba)₂ (339 mg, 0.37 mmol). The resulting mixture was stirred at RT overnight, diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica (50% EtOAc in petroleum ether) followed by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 399.1 found, 399.2 required.

TABLE 2 The following compounds were prepared according to the general procedure provided in Example 8 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 11

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4- ((5-fluoropyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)methanone Calc'd 367.2, found 367.2 12

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4- (isoquinolin-1-ylamino)-2-methylpyrrolidin- 1-yl)methanone Calc'd 399.2, found 399.2 14

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2- methyl-4-((4-(trifluoromethyl)pyridin-2- yl)amino)pyrrolidin-1-yl)methanone Calc'd 417.2 found 417.1 15

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4- ((4-chloropyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)methanone Calc'd 383.1 found 383.1 16

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2- methyl-4-((4-methylpyridin-2- yl)amino)pyrrolidin-1-yl)methanone Calc'd 363.2 found 363.2 17

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4- ((4-fluoropyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)methanone Calc'd 367.2 found 367.1 18

2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2- yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)- 4-methoxynicotinonitrile Calc'd 404.2 found 404.2 19

2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2- yl)benzoyl)-5-methylpyrrolidin-3- yl)amino)isonicotinonitrile Calc'd 374.2 found 374.1

Example 20

(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-4-((4-isopropoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone Step 1: 2-chloro-4-isopropoxypyridine (13)

To a solution of 2-chloropyridin-4-ol (4 g, 30.9 mmol) in DMF (50 mL) at RT, were added 2-iodopropane (7.59 g, 46.3 mmol) and potassium carbonate (8.54 g, 61.8 mmol) and the resulting mixture stirred at RT overnight. The reaction mixture was diluted with EtOAc (500 mL), washed with brine (1.0 L×5), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the crude product, purified by chromatography on silica (petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 172.0 found, 172.0 required.

Step 2: (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-isopropoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone

A mixture of (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (Example 8 step 6) (100 mg, 0.369 mmol), the product from step 1 (63 mg, 0.369 mmol), Cs₂CO₃ (300 mg, 0.92 mmol), X-phos (36 mg, 0.074 mmol) and Pd₂(dba)₃ (50 mg, 0.055 mmol) in DMF (3 mL) was stirred at 100° C. under N₂ atmosphere for 5 hours. The mixture reaction was filtered and the filtrate purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 407.2 found, 407.2 required.

TABLE 3 The following compound were prepared according to the general procedure provided in Example 20 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 21

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)- 4-((4-ethoxypyridin-2-yl)amino)-2- methylpyrrolidin-1-yl)methanone Calc'd 393.2, found 393.2

Example 22

N-((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)-N-(4-cyanopyridin-2-yl)acetamide

To a solution of 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile (Example 19) (70 mg, 0.19 mmol) in DCM (3 mL) at 0° C. was added DIPEA (73 mg, 0.56 mmol), the mixture was stirred for 30 mins, then acetyl chloride (14 mg, 0.19 mmol) added. The mixture was stirred at RT for 9 h, diluted with DCM (15 mL), washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give crude product which was purified by Prep-HPLC to give the title compound. LRMS m/z (M+H) 416.2 found, 416.2 required.

Example 23

2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)amino)isonicotinonitrile

To a solution of 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile (Example 19) (70 mg, 0.19 mmol) in DMF (3 mL) at 0° C., was added NaH (8 mg, 0.2 mmol). After stirring for 30 mins, iodomethane (43 mg, 0.3 mmol) was added and stirring continued for for 9 h at RT. The mixture was diluted with DCM (15 mL), washed with brine, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by Prep-HPLC to give the title compound. LRMS m/z (M+H) 388.2 found, 388.2 required.

Example 24

1-(2-((2R,4R)-4-((4-Methoxypyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclopropanecarbonitrile Step 1: (2R,4R)-tert-Butyl 4-amino-2-methylpyrrolidine-1-carboxylate (14)

To a solution of (2R,4R)-tert-butyl 4-azido-2-methylpyrrolidine-1-carboxylate (Example 8 step 2) (1.8 g, 8.5 mmol) in EtOAc (50 mL) at RT was added Pd/C (200 mg) and the mixture hydrogenated at 1 atm. H₂ for 9 h. The mixture was filtered and the filtrate concentrated in vacuo to give the crude product as an oil, used in the next step without purification. LRMS m/z (M+H) 201.2 found, 201.2 required.

Step 2: (2R,4R)-tert-Butyl 4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidine-1-carboxylate (15)

A mixture of the product from step 1 (100 mg, 0.499 mmol) and 2-fluoro-4-methoxypyridine (100 mg, 0.787 mmol) was stirred at 160° C. for 90 mins. After cooling to RT, the mixture was purified by Prep-TLC (9% methanol in DCM) to give the title compound as an oil. LRMS m/z (M+H) 308.2 found, 308.2 required.

Step 3: 4-Methoxy-N-((3R,5R)-5-methylpyrrolidin-3-yl)pyridin-2-amine (16)

To a solution of the product from step 2 (120 mg, 0.391 mmol) in DCM (10 mL) at 0° C. was added TFA (4 mL) dropwise. The resulting mixture was stirred at RT for 2 h then concentrated in vacuo to give the product as an oil used in the next step without purification. LRMS m/z (M+H) 208.2 found, 208.2 required.

Step 4: 1-(2-((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclopropanecarbonitrile (Example 24)

A mixture of the product of step 3 (100 mg, 0.483 mmol), 2-(1-cyanocyclopropyl)benzoic acid (Intermediate A) (90 mg, 0.483 mmol), HATU (220 mg, 0.580 mmol) and DIPEA (218 mg, 1.69 mmol) in DCM (2 mL) was stirred at RT overnight. The mixture was concentrated in vacuo and the residue purified by Prep-HPLC to give the title compound Example 27 as a solid. LRMS m/z (M+H) 377.2 found, 377.2 required.

Example 25

Step 1: (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone

To a solution of 3-methoxy-N-((3R,5R)-5-methylpyrrolidin-3-yl)pyridin-2-amine (Example 24, step 3) (25 mg, 0.121 mmol) in DMF (500 μL) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (27 mg, 0.145 mmol), followed by EDC hydrochloride (46 mg, 0.241 mmol), DIEA (31 mg, 0.241 mmol), and HOAt (16.42 mg, 0.121 mmol). The solution was stirred overnight at 50° C., cooled, diluted with water (2 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by chromatography on silica (10-60% ethyl acetate) to give the title compound as a solid. LRMS m/z (M+H) 379.2 found, 379.2 required.

TABLE 4 The following compound were prepared according to the general procedure provided in Example 25 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 26

((2R,4R)-4-((4-Methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1- yl)(2-((methylsulfonyl)methyl)- phenyl)methanone Calc'd 404.2 found 404.1

Example 27

(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone Step 1: 2-chloro-4-(difluoromethyl)pyridine (17)

To a solution of 2-chloroisonicotinaldehyde (230 mg, 1.60 mmol) in DCM (3 mL) was added DAST (773 mg, 4.80 mmol) at 0° C. under N₂ and the mixture stirred at 0° C. for 1 h. Saturated aq. NaHCO₃ was added and the mixture extracted with EtOAc (30 mL×3). The combined organic layers were dried over MgSO₄, filtered, the filtrate concentrated in vacuo and the crude product purified by chromatography on silica (50% EtOAc in petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 164.1 found, 164.1 required.

Step 2: (2S,4R)-tert-Butyl 2-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyrrolidine-1-carboxylate (18)

A mixture of the product from step 1 (100 mg, 0.6 mmol), (2S,4R)-tert-butyl 2-amino-4-methylpyrrolidine-1-carboxylate (Example 25 step 1) (120 mg, 0.6 mmol), X-phos (572 mg, 1.2 mmol), Cs₂CO₃ (391 mg, 1.2 mmol) and Pd₂(dba)₃ (10 mg) in DMF (4 mL) was heated at 110° C. under N₂ for 16h. The cooled mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over MgSO₄, filtered, the filtrate concentrated in vacuo and the crude product purified by Prep-TLC (25% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H-56) 272.1 found, 328.2 required.

Step 3: 4-(Difluoromethyl)-N-((2R,4R)-4-methylpyrrolidin-2-yl)pyridin-2-amine (19)

To a solution of the product from step 2 (110 mg, 0.340 mmol) in DCM (5 mL) at 0° C. was added TFA (5 mL) and the mixture stirred at RT for 1h. The mixture was concentrated to give the title compound as an oil, which was used directly in the next step. LRMS m/z (M+H) 228.1 found, 228.1 required.

Step 4: (2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone

A mixture of 2-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid (Intermediate D) (30.0 mg, 0.15 mmol), DIPEA (58 mg, 0.45 mmol) and HATU (114 mg, 0.3 mmol) in DCM (3 mL) was stirred at RT for 10 min, followed by addition of the product from step 3 (34 mg, 0.15 mmol). The resulting mixture was stirred at RT for 2h, concentrated in vacuo and purified by Prep-HPLC to give the title compound as an oil. LRMS m/z (M+H) 405.1 found, 405.1 required.

TABLE 5 The following compound were prepared according to the general procedure provided in Example 27, replacing Intermediate D in step 4 with Intermediate F, and procedures herein. The satarting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 28

(4-(2H-1,2,3-triazol-2- yl)thiophen-3-yl)((2R,4R)-4-((4- (difluoromethyl)pyridin-2- yl)amino)-2-methylpyrrolidin-1- yl)methanone Calc'd 405.1, found 405.1

Example 29

2-(((3R,5R)-1-(2-(2H-tetrazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile Step 1: (2R,4R)-tert-Butyl 4-((4-cyanopyridin-2-yl)amino)-2-methylpyrrolidine-1-carboxylate (20)

To a solution of (2R,4R)-tert-butyl 4-amino-2-methylpyrrolidine-1-carboxylate (Example 25 step 1) (200 mg, 1.0 mmol) in DMF (10 mL) were added 2-chloropyridine-4-carbonitrile (208 mg, 1.5 mmol), Pd(dba)₂ (20 mg), X-phos (40 mg) and Cs₂CO₃ (975 mg, 3 mmol). The mixture was stirred at 90° C. for 9 hours under N₂, cooled to RT and diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo and the crude product purified by Prep-TLC (50% EtOAc in petroleum ether) to give the title compound. LRMS m/z (M+H) 303.2 found, 303.2 required.

Step 2: 2-(((3R,5R)-5-Methylpyrrolidin-3-yl)amino)isonicotinonitrile (21)

A solution of the product from step 1 (140 mg, 0.46 mmol) in TFA/DCM (3 mL/3 mL) was stirred at RT for 0.5 hours and concentrated in vacuo to give the product (70 mg) used directly in the next step. LRMS m/z (M+H) 203.2 found, 203.2 required.

Step 3: 2-(((3R,5R)-1-(2-(2H-tetrazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile

A mixture of 2-(2H-tetrazol-2-yl)benzoic acid (Intermediate C) (50 mg, 0.27 mmol), HATU (148 mg, 0.39 mmol), DIPEA (100 mg, 0.78 mmol) and the product from step 2 (78 mg, 0.27 mmol) in DMF (5 mL) was stirred at RT for 9 hours under N₂. The mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo to give the crude product, purified by Prep-HPLC to give the title compound. LRMS m/z (M+H) 375.2 found, 375.2 required.

TABLE 6 The following compounds were prepared according to the general procedure provided in Example 29 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 30

2-(((3R,5R)-5-Methyl-1-(2- (pyrimidin-2-yl)benzoyl)pyrrolidin-3- yl)amino)isonicotinonitrile Calc'd 385.2 found 385.1

Example 31

(2-(2H-1,23-Triazol-2-yl)phen)((2R,4R)-4-((4-bromopyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone

To a solution of (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (Example 8 step 6) (100 mg, 0.369 mmol) in DMF (2.5 mL) were added 4-bromo-2-fluoropyridine (195 mg, 1.11 mmol) and triethylamine (0.3 mL). The resulting mixture was stirred under microwave irradiation at 140° C. for 20 mins, cooled to RT, filtered and the filtrate purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 427.1, 429.1 found, 427.1, 429.1 required.

Example 32

Methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate

A mixture of (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl) methanone (Example 8 step 6) (100 mg, 0.37 mmol), methyl 2-fluoro-4-methoxynicotinate (69 mg, 0.37 mmol), triethylamine (112 mg, 1.11 mmol) in NMP (5 mL) was heated under microwave irradiation at 180° C. for 20 minutes. After cooling to RT, the mixture was filtered and the filtrate purified by Prep-HPLC to give the title compound as an oil. LRMS m/z (M+H) 437.2 found, 437.2 required.

Example 33

Ethyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate Step 1: 2-Chloro-4-methoxypyridine (22)

A mixture of 2-chloropyridin-4-ol (5 g, 38.7 mmol), K₂CO₃ (10.7 g, 77.5 mmol) and iodomethane (10.9 g, 77.5 mmol) in DMF (70 mL) was stirred at RT for 15 h, diluted with EtOAc (100 mL) and filtered. The filtrate was washed with water, brine, dried over MgSO₄ and filtered. The filtrate was concentrated in vacuo to give the crude product, which was purified by chromatography on silica (5-50% EtOAc in petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 144.0 found, 144.0 required.

Step 2: 2-Chloro-4-methoxynicotinic acid (23)

To a solution of the product from step 1 (3.68 g, 25.7 mmol) in THF (50 mL) at −78° C. was added dropwise, n-BuLi (12 mL, 30 mmol). After stirring at −78° C. for 30 min, the mixture was added to dry-ice quickly and the mixture adjusted to pH ˜3 with 1M HCl. The mixture was diluted with EtOAc (70 mL), washed with water, brine, dried over MgSO₄ and filtered. The filtrate was concentrated in vacuo to give the crude product as a solid used directly in the next step. LRMS m/z (M+H) 188.0 found, 188.0 required.

Step 3: Ethyl 2-chloro-4-methoxynicotinate (24)

To a solution of the product from step 2 (2.2 g, 11.8 mmol) in ethanol (30 mL) was added conc. H₂SO₄ at RT The mixture was stirred for 12 h, diluted with EtOAc (100 mL) and the pH of the mixture adjusted ˜7 with 1M aq. Na₂CO₃. The organic layer was washed with water, brine, dried over MgSO₄, and filtered. The filtrate was concentrated in vacuo to give the crude product as a solid which was used directly in the next step. LRMS m/z (M+H) 216.0 found, 216.0 required.

Step 4: Ethyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate

A mixture of (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl) methanone (Example 8 step 6) (80 mg, 0.28 mmol), ethyl 2-chloro-4-methoxynicotinate (74 mg, 0.34 mmol), Xant-phos (60 mg, 0.1 mmol), Cs₂CO₃ (182 mg, 0.56 mmol), Pd₂(dba)₃(52 mg, 0.06 mmol) in dioxane (4 mL) was heated at 120° C. for 16 h. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, the filtrate was concentrated in vacuo and the crude product purified by Prep-HPLC to give the title compound as an oil. LRMS m/z (M+H) 451.2 found, 451.2 required.

TABLE 7 The following compounds were prepared according to the general procedure provided in Example 29 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 34

Methyl 2-(((3R,5R)-1-(2-(2H- 1,2,3-triazol-2-yl)benzoyl)-5- methylpyrrolidin-3-yl)amino)-4- ethoxynicotinate Calc'd 451.2, found 451.2

Example 35

(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-4-((4-bromopyridin-2-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)methanone Step 1: tert-Butyl ((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)carbamate (25)

To a solution of tert-butyl ((3R,5S)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)carbamate (Example 8 step 5) (2 g, 5.39 mmol) in DMF (20 mL) was added NaH (388 mg, 16.2 mmol) in two portions at 0° C. The mixture was stirred at 0° C. for 30 mins and iodomethane (1.15 g, 8.09 mmol) was added dropwise at 0° C. The resulting mixture was stirred at RT overnight. The mixture was diluted with water (40 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography column (20% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 386.2 found, 386.2 required.

Step 2: (2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-(methylamino)pyrrolidin-1-yl)methanone (26)

To a solution of the product from step 1 (1.8 g, 4.68 mmol) in DCM (30 mL) at 0° C. was added TFA (20 mL) dropwise. The resulting mixture was stirred at RT for 2 h, concentrated in vacuo, diluted with DCM (50 mL), stirred and triethylamine added dropwise to pH=8. The mixture was diluted with water (30 mL) and extracted with DCM (50 mL×10). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica (9% methanol in DCM) to give the title compound as an oil. LRMS m/z (M+H) 286.2 found, 286.2 required.

Step 3: (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-bromopyridin-2-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)methanone

To a solution of the product from step 2 (100 mg, 0.351 mmol) in DMF (2.5 mL) were added 4-bromo-2-fluoropyridine (185 mg, 1.05 mmol) and triethylamine (0.3 mL). The resulting mixture was heated under microwave irradiation at 140° C. for 20 mins, cooled to RT, filtered and the filtrate purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 441.1, 443.1 found, 441.1, 443.1 required.

Example 36

2-(((3R,5R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-ethylisonicotinonitrile Step 1: 2-Fluoro-4-iodo-3-methylpyridine (27)

To a solution 2-fluoropyridine (46 g, 0.47 mol) in THF (500 mL) at −70° C. was added dropwise LDA (260 mL, 0.52 mol). After stirring for 40 min, a solution of I₂ (126 g, 0.496 mol) in THF (300 mL) was added dropwise. After 2 h, LDA (260 mL, 0.52 mol) was added dropwise at −70° C. The resulting mixture was stirred at −70° C. for 30 min, a solution of MeI (128.5 g) in THF (50 mL) was added dropwise. The resulting mixture was stirred at −70° C. for 3 h, sat. aq. NH4C1 added and the mixture extracted with EtOAc (200 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 238.1 found, 238.1 required.

Step 2: 2-Fluoro-3-methylisonicotinonitrile (28)

A mixture of the product from step 1 (30 g, 0.127 mol) and CuCN (28.5 g, 0.317 mol) in NMP (100 mL) was stirred at 120° C. overnight, the cooled mixture filtered, water (200 mL) added and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 137.1 found, 137.1 required.

Step 3: 2-(((3R,5R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methylisonicotinonitrile

A mixture of the product from step 2 (76 mg, 0.558 mmol), (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (Example 8 step 6) (100 mg, 0.369 mmol) and triethylamine (112 mg, 1.11 mmol) in DMSO was heated at 140° C. under microwave irradiation for 20 min. The mixture was cooled to RT, filtered and the filtrate purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 388.1 found, 388.2 required.

Example 37

2-(((3R,5R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)amino)-3-methylisonicotinonitrile

To a solution of 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methylisonicotinonitrile (Example 36) (70 mg, 0.181 mmol) in DMF (3 mL) at 0° C. was added NaH (8 mg, 0.2 mmol), the mixture was stirred for 30 min, then iodomethane (43 mg, 0.3 mmol) added. The reaction mixture was stirred at RT for 9 h, diluted with DCM (15 mL), washed with brine, dried over sodium Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the crude product purified by Prep-HPLC to give the title compound. LRMS m/z (M+H) 402.1 found, 402.2 required.

Example 38

Methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-cyanonicotinate Step 1: 2-Fluoro-4-iodonicotinaldehyde (29)

To a solution of 2-fluoropyridine (30 g, 0.309 mol) in THF (500 mL) at −70° C. was added LDA (170 mL, 0.34 mol) dropwise. After 40 min, a solution of I₂ (82 g, 0.323 mol) in THF (200 mL) was added dropwise at −70° C. and the mixture stirred at −70° C. for 1 h. LDA (170 mL, 0.34 mol) was added and after 30 min, a solution of ethyl formate (25 g, 0.34 mol) in THF (50 mL) was added dropwise. The resulting mixture was stirred at −70° C. under N₂ for 2 h, sat. aq. NH₄Cl added and the mixture extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the crude product, purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 252.1 found, 252.1 required.

Step 2: 2-Fluoro-4-iodonicotinic acid (30)

To a mixture of the product from step 1 (25 g, 99.6 mmol) in t-BuOH/water (240/80 mL) at RT was added 2-methyl-2-butene (105 mL), NaClO₂ (45 g, 498 mmol) and NaH₂PO4 (120 mg, 100 mmol) and the resulting mixture stirred at RT for 16 h. Saturated aq. Na₂SO₃ was added, the mixture acidified to pH 3-4 with 2M HCl and the mixture extracted with EtOAc (200 mL×3). The combined organic layers were dried over Na₂SO₄, filtered, the filtrate concentrated in vacuo to give the title compound as an oil, which was used in the next step directly. LRMS m/z (M+H) 268.1 found, 268.1 required.

Step 3: Methyl 2-fluoro-4-iodonicotinate (31)

To a solution of the product from step 2 (23.5 g, 88 mmol) in methanol (300 mL) was added dropwise TMSCHN₂ (220 mL, 440 mmol) at 0-5° C. under N₂. After addition was complete, the mixture was stirred at RT for 16 hrs, water was added and the mixture extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 282.1 found, 282.1 required.

Step 4: Methyl 4-cyano-2-fluoronicotinate (32)

A mixture of the product from step 3 (9.0 g, 32.03 mmol) and CuCN (7.2 g, 80 mmol) in NMP (150 mL) was heated to 120° C. 16 h. The cooled mixture was diluted with water (500 mL). filtered and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as an oil. LRMS m/z (M+H) 181.1 found, 181.1 required.

Step 5: Methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-cyanonicotinate

A mixture of the product from step 4 (150 mg, 0.833 mmol), (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (Example 8 step 6) (150 mg, 0.554 mmol) and triethylamine (168 mg, 1.66 mmol) in DMSO was heated under microwave irradiation at 140° C. for 20 min. After cooling to RT, the mixture was filtered and the filtrate was purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 432.1 found, 432.2 required.

Example 39

2-(((3R,5R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methoxyisonicotinonitrile Step 1: 2-Chloro-3-methoxypyridine (33)

To a mixture of 2-chloropyridin-3-ol (1 g, 7.72 mmol) and potassium carbonate (1.28 g, 9.28 mmol) in DMF (10 mL) at RT was added MeI (1.2 g, 8.45 mmol) and the resulting mixture was stirred at RT overnight. Water (50 mL) was added and the mixture extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, dried over Na₂SO₄, the mixture filtered and the filtrate concentrated in vacuo to give the title compound as an oil, which was used directly in the next step. LRMS m/z (M+H) 143.1 found, 143.1 required.

Step 2: 2-Chloro-4-iodo-3-methoxypyridine (34)

To a solution of the product of step 1 (12.8 g, 89.16 mmol) in THF (100 mL) at −70° C. was added LDA (67 mL) dropwise. After stirring for 40 min, a solution of I₂ (29.5 g, 116 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at −70° C. for 5 h, sat. aq. NH₄Cl added and the mixture extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 269.1 found, 269.1 required.

Step 3: 2-Chloro-3-methoxyisonicotinonitrile (35)

A mixture of the product from step 2 (6.8 g, 25.23 mmol) and CuCN (5.7 g, 63.33 mmol) in NMP (100 mL) was heated at 120° C. for 4.5 h. Water (250 mL) was added to the cooled mixture and the resulting mixture extracted with EtOAc (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (10% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 169.1 found, 169.1 required.

Step 4: 2-(((3R,5R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzo)-5-methylpyrrolidin-3-yl)amino)-3-methoxyisonicotinonitrile

A mixture of (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)methanone (Example 8 step 6) (100 mg, 0.369 mmol), the product from step 3 (75.3 mg, 0.445 mmol), X-phos (35.2 mg, 0.073 mmol), Pd₂(dba)₃ (68.1 mg, 0.074 mmol) and Cs₂CO₃ (300 mg, 0.923 mmol) in DMF (5 mL) was stirred at 100° C. under N for 4 h. The mixture was cooled to RT., filtered and the filtrate purified by Prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 404.1 found, 404.2 required.

Example 40

(3-(1H-Pyrazol-1-yl)pyridin-2-yl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone

To 3-methoxy-N-((3R,5R)-5-methylpyrrolidin-3-yl)pyridin-2-amine (Example 26, step 3) (25 mg, 0.121 mmol) in DMF (500 μL) was added 2-(1H-pyrazol-1-yl)nicotinic acid (29 mg, 0.145 mmol), followed by EDC hydrochloride (46 mg, 0.241 mmol), DIPEA (31 mg, 0.241 mmol), and HOAt (16 mg, 0.121 mmol). The reaction mixture was stirred at 50° C. overnight, cooled, diluted with water (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO₄, filtered and the filtrate concentrated in vacuo. The crude product was purified by chromatography on silica (10-60% EtOAc) to give the title compound as a solid. LRMS m/z Calc'd 379.2, found 379.2.

TABLE 8 The following compounds were prepared according to the general procedure provided in Example 40 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

LRMS or HRMS Ex. R Name (M + H⁺) 41

((2R,4R)-4-((3-Methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1-yl)(3- (4-methyl-1H-pyrazol-1-yl)pyridin-2- yl)methanone Calc'd 393.2, found 393.2 42

((2R,4R)-4-((3-Methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1-yl)(2- (5-methyl-1,2,4-oxadiazol-3- yl)phenyl)methanone Calc'd 394.2, found 394.2 43

(3-(1H-Pyrazol-1-yl)pyrazin-2- yl)((2R,4R)-4-((3-methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1- yl)methanone Calc'd 380.2, found 380.2 44

((2R,4R)-4-((3-Methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1-yl)(3- (pyridin-2-yl)pyrazin-2-yl)methanone Calc'd 391.2, found 391.2 45

((2R,4R)-4-((4-Methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1-yl)(2- (3-methyl-1,2,4-oxadiazol-5- yl)phenyl)methanone Calc'd 394.2, found 394.2 46

((2R,4R)-4-((4-Methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1-yl)(2- propylphenyl)methanone Calc'd 354.2, found 354.2 47

((2S,4S)-4-((4-methoxypyridin-2- yl)amino)-2-methylpyrrolidin-1-yl)(2- (trifluoromethoxy)phenyl)methanone Calc'd 396.2, found 396.2

TABLE 9 The following table shows representative data for the compounds of the Examples as orexin receptor antagonists as determined by the assays described herein. hOX2R FLIPR hOX1R FLIPR Example IC₅₀ (nM) IC₅₀ (nM) 1 58.3 4042 2 65.1 10000 3 367.0 >10000 4 519.9 >10000 5 624.8 >10000 6 989.4 >10000 7 1996 >10000 9 13.6 1632 11 174.9 6289 12 15.3 257 14 26.3 1086 15 23.1 1156 16 75.9 4067 17 119 >10000 18 167 >10000 19 22.9 >10000 20 39.8 2803 21 31.5 3990 23 120/5 >10000 24 23.9 2718 25 36.1 3385 27 67.8 >10000 28 101.8 >10000 29 301.8 >10000 30 31.1 >10000 31 11.2 1152 32 29.7 6748 33 31.1 4072 34 66.2 >10000 35 136.1 2250 36 23.6 3353 37 3207 >10000 38 14.6 1548 39 40.8 >10000 41 758 10000 42 500 10000 43 1500 10000 44 2373 10000 45 278 10000 46 179 9833 47 41 3954

With respect to other compounds such as those disclosed in U.S. Pat. No. 8,357,709 or WO 2010/048012, it would be desirable that the present compounds exhibit unexpected properties, such as increased selectivity at the orexin-2 receptor relative to the orexin-1 receptor. For example, relative to compounds of U.S. Pat. No. 8,357,709 or WO2010/048012, the compounds of the examples possess greater selectivity for the orexin-2 receptor than for the orexin-1 receptor.

As indicated by the data herein, the compounds of the present examples provide greater functional selectivity for the orexin-2 receptor over the orexin-1 receptor. The distinction in potency between the orexin-2 receptor and the orexin-1 receptor in the whole cell FLIPR functional assay provides enhanced predictive value for determining in vivo efficacy. Increasing the functional selectivity for the orexin-2 receptor reduces the potential for dual receptor antagonism in vivo. Such greater functional selectivity may provide benefits over other orexin receptor antagonists that are known in the art.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. 

1. A compound of the formula I:

wherein: A is selected from the group consisting of phenyl, naphthyl and heteroaryl; X is N or CH; each of R^(1a), R^(1b) and R^(1c) is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one to three substituents independently selected from R⁴, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R⁴, (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted or substituted with one to three substituents independently selected from R⁴, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted or substituted with one to three substituents independently selected from R⁴, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one to three substituents independently selected from R⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is unsubstituted or substituted with one to three substituents independently selected from R⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected from the group consisting of: (a) hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R⁴, (c) C₃₋₆alkenyl, which is unsubstituted or substituted with R⁴, (d) C₃₋₆alkynyl, which is unsubstituted or substituted with R⁴, (e) C₃₋₆cycloalkyl which is unsubstituted or substituted with R⁴, (f) phenyl, which is unsubstituted or substituted with R⁴, and (g) heterocycle, which is unsubstituted or substituted with R⁴, (11) —S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN, and (15) —NO₂; R² is selected from hydrogen, C₁₋₆alkyl, and —(C═O)—C₁₋₆alkyl; R³ is selected from hydrogen and C₁₋₆alkyl; R⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen, (3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6) —O(C═O)—C₁₋₆alkyl, (7) —NH₂, (8) —NH—C₁₋₆alkyl, (9) —NO₂, (10) phenyl, (11) heterocycle, (12) —CO₂H, and (13) —CN; R⁵ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —CN, (3) C₁₋₆alkyl, which is unsubstituted or substituted with halogen or phenyl, (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen or phenyl, (5) —O—C₃₋₆cycloalkyl, which is unsubstituted or substituted with C₁₋₆alkyl, halogen or phenyl, and (6) —(C═O)—O—C₁₋₆alkyl; R⁶ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —CN, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen or phenyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen or phenyl, (6) —O—C₃₋₆cycloalkyl, which is unsubstituted or substituted with C₁₋₆alkyl, halogen or phenyl, and or R⁵ and R⁶ may be joined together with the carbon atoms to which they are attached to form a 6-membered aromatic ring, which is unsubstituted or substituted with one or two C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R^(1a), R^(1b) and R^(1c) are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (6) —CN, and (7) heteroaryl, wherein heteroaryl is selected from imidazolyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl, and triazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R² is hydrogen and R³ is methyl.
 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁵ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C₁₋₆alkyl, which is unsubstituted or substituted with halogen, (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen, and (5) —(C═O)—O—C₁₋₆alkyl.
 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁵ is selected from the group consisting of: hydrogen, fluoro, methyl, and methoxy.
 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁶ is selected from the group consisting of: (1) —CN, and (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen.
 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R⁶ is selected from the group consisting of: —CN, methyl, methoxy, and difluoroethoxy.
 9. A compound which is selected from the group consisting of: 1-(2-((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclobutcarbonitrile; 1-(2-((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclopropanecarbonitrile; (2-(2H-tetrazol-2-yl)phenyl)((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-(6-fluoropyridin-2-yl)oxazol-2-yl)-2-methylpiperidin-1-yl)methanone; ((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone; ((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-ethoxypyridin-3-yl)methanone; ((2R,4R)-4-((4-(2,2-difluoroethoxy)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2,3-dihydro-1H-inden-4-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-(quinolin-2-ylamino)pyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((5-fluoropyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-(isoquinolin-1-ylamino)-2-methylpyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-chloropyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-2-methyl-4-((4-methylpyridin-2-yl)amino)pyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-fluoropyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinonitrile; 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-isopropoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-ethoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; N-((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)-N-(4-cyanopyridin-2-yl)acetamide; 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)amino)isonicotinonitrile; 1-(2-((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidine-1-carbonyl)phenyl)cyclopropanecarbonitrile; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; ((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-((methylsulfonyl)methyl)phenyl)methanone; (2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; (4-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,4R)-4-((4-(difluoromethyl)pyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; 2-(((3R,5R)-1-(2-(2H-tetrazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)isonicotinonitrile; 2-(((3R,5R)-5-methyl-1-(2-(pyrimidin-2-yl)benzoyl)pyrrolidin-3-yl)amino)isonicotinonitrile; (2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,4R)-4-((4-bromopyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate; ethyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate; methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-methoxynicotinate (2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,4R)-4-((4-bromopyridin-2-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)methanone; 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methylisonicotinonitrile; 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)(methyl)amino)-3-methylisonicotinonitrile; methyl 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-4-cyanonicotinate; 2-(((3R,5R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-5-methylpyrrolidin-3-yl)amino)-3-methoxyisonicotinonitrile; (3-(1H-pyrazol-1-yl)pyridin-2-yl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; ((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(3-(4-methyl-H-pyrazol-1-yl)pyridin-2-yl)methanone; ((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)methanone; (3-(1H-pyrazol-1-yl)pyrazin-2-yl)((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)methanone; ((2R,4R)-4-((3-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(3-(pyridin-2-yl)pyrazin-2-yl)methanone; ((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanone; ((2R,4R)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-propylphenyl)methanone; and ((2 S,4 S)-4-((4-methoxypyridin-2-yl)amino)-2-methylpyrrolidin-1-yl)(2-(trifluoromethoxy)phenyl)methanone; or a pharmaceutically acceptable salt thereof.
 10. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 11. (canceled)
 12. (canceled)
 13. A method for enhancing the quality of sleep in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
 14. A method for treating insomnia in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
 15. A method for treating or controlling obesity in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. 